Project Details
Projekt
Neutrophil extracellular traps orchestrate the immune response in Inflammatory Bowel Diseases
Subject Area
Gastroenterology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 190140969
The functional contribution of neutrophil granulocytes to the pathogenesis of inflammatory Bowel Diseases (IBD) such as Crohn's Disease and Ulcerative Colitis has been a matter of debate during the last decades. It has been proposed that neutrophil dysfunction is an important contributor to the pathogenesis of IBD. Specific defects of granulocyte function are associated with fistulizing enterocolitis in humans. However, the cellular and molecular mechanisms leading to intestinal disease in the context of granulocyte dysfunction remain elusive. Several years ago, a novel effector mechanism of neutrophil granulocytes has been described by which neutrophils extrude chromatin and form neutrophil extracellular traps (NETs). This process depends on reactive oxygen species (ROS) and histone citrullination by peptidyl arginine deiminase 4 (PAD14). Pro- and anti-inflammatory effects of NETs and NET aggregates (aggNETs) have been described recently, yet the knowledge about the functional role of this process in intestinal inflammation is scarce. In this project we will delineate the functional role of NETs in the course of intestinal inflammation in mice and IBD in humans. Firstly, we will make use of a set of genetically defined models in order to decipher the roles of histone citrullination, ROS generation in neutrophils and the combined defect of both effector mechanisms. We argue that the analysis of various models of intestinal inflammation will provide a sophisticated understanding of NETosis in enteric diseases. Secondly, we will analyze the capacity of IBD patient-derived neutrophils to produce NETs and aggNETs in response to a defined set of stimuli and interpret the findings in the context of the clinical course of disease. We aim to further validate a routine NETosis assay for clinical practice. The identification of immunodeficient IBD patients with neutrophil dysfunction may strongly impact therapeutic decisions in patient care.
DFG Programme
Clinical Research Units
